DOI: 10.1002/alz.070996 ISSN: 1552-5260

Age related neuropathology in a novel mouse model of Adult‐onset leukoencephalopathy

Sepideh Kiani Shabestari, Hamsi Radhakrishnan, Winston Chang Rothermich, Joia Kai Capocchi, Amandine Jullienne, Jasmine Nguyen, Kayla Nhi Tran, Jesse R. Pascual, Alessandra Cadete Martini, Elizabeth Head, David A Hume, Clare Pridans, Andre Obenaus, Craig E.L. Stark, Hayk Davtyan, Mathew Blurton‐Jones
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Geriatrics and Gerontology
  • Neurology (clinical)
  • Developmental Neuroscience
  • Health Policy
  • Epidemiology



Adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare human disease that is caused by mutations in CSF1R, a gene that is critical for the differentiation, proliferation, and survival of microglia. ALSP patients typically develop dementia, motor impairments, and seizures during their 30s or 40s. Upon autopsy, patients’ brains exhibit decreased numbers of microglia, white matter atrophy, astrocytosis, axonal spheroids, enlarged ventricles, and calcification. Two recent reports have further described rare cases of homozygous CSF1R mutations that lead to perinatal lethality, a complete absence of microglia, and an acceleration of ALSP pathologies. Unfortunately, there is currently no effective treatment for this devastating disease.


To better understand the role of microglia in the development and progression of ALSP we utilized the ‘FIRE’ mouse model that harbors a homozygous deletion in a microglial‐specific enhancer within the CSF1R gene.


Surprisingly, at 2 months of age, despite absence of microglia, FIRE mice exhibit normal brain gross anatomy, minimal white matter alterations, and little to no pathology. However, by 10‐months of age FIRE mice exhibit many of the pathologies and symptoms observed in ALSP patients, including axonal spheroids, calcification, demyelination, seizures, and behavioral deficits. Importantly, postnatal transplantation of wildtype murine microglia prevents nearly all of these pathologies, demonstrating the importance of decreased microglial numbers on the development of ALSP. Additional ongoing examinations of 2‐ and 10‐month‐old FIRE mice are exploring the sex‐related impact of microglia absence on synaptic density and utilizing MRI imaging to examine white matter integrity and calcification.


Taken together, these data suggest that aged FIRE mice may provide a novel and informative, albeit rapidly progressing, model of human ALSP.

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